The Indiana Regional Cardiovascular Cell Therapy Center (IRCCTC) will extend the work of the Cardiovascular Cell Therapy Research Network, particularly in the area of peripheral arterial disease (PAD). Critical limb ischemia (CLI) results in at least 50,000 amputations annually, with a cost estimated at $4.3 billion/year. In a recent Phase l/ll trial we have demonstrated safety and feasibility of intra-muscular injection of autologous bone marrow mononuclear cells (ABMNC) in patients with CLI, and provided initial evidence that this treatment improves amputation-free survival at one year. Although these results are promising, there is an opportunity to improve the effectiveness of cell therapy for CLI by identifying more potent sources of progenitor cells and by evaluating functional characteristics of transplanted cells. While many cardiovascular cell-based trials have focused on ABMNC, adipose stromal cells (ASCs) have demonstrated qualities particularly suitable for promoting limb salvage in CLI. In addition, cord blood mononuclear cells (CBMNC) have been shown to include vasculogenic endothelial progenitor cells, to augment perfusion in ischemic limbs, and to be tolerated by an immunocompetent host. CLI presents an excellent opportunity to examine these two readily accessible cell populations with regard to suitability for cardiovascular cell therapy, in that there exist no other options fo salvage of the index limb, potential adverse events are not immediately life-threatening, and tissue can be obtained for analysis in the event of amputation. Also, mechanisms promoting limb salvage in CLI have relevance to myocardial ischemic syndromes. In this application for a new Regional Center, we propose two protocols, respectively evaluating allogeneic cord blood mononuclear cells and adipose stromal cells as potential therapies for CLI. Aim 1 will evaluate whether CBMNC are superior to placebo in promoting amputation-free survival at 1 year in subjects with critical limb ischemia of Rutherford Category 4, and no /high-risk options for standard revascularization. Aim 2 will test the hypothesis that adipose stromal cells (ASCs) are safe and may increase time to amputation in subjects with critical limb ischemia and ulcers / tissue loss (Rutherford Category 5-6).